Detergent-mediated protein aggregation
Detergent-mediated protein aggregation
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DOI：
10.1016/j.chemphyslip.2013.02.005
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发表时间：
2013-04-01
影响因子：
3.4
通讯作者：
Pomes, Regis
中科院分区：
文献类型：
--
作者：
Neale, Chris;Ghanei, Hamed;Pomes, Regis
由于洗涤剂通常用于溶剂化膜蛋白进行结构评价，因此，与脂质双层的天然环境相比，人们一直致力于评估洗涤剂胶束所赋予的构象偏差。在这里，我们进行了六个500 ns的模拟系统与> 600，000个原子，以调查周围的多个分子的完整的膜蛋白PagP的十二烷基磷酸胆碱洗涤剂的自发自组装。这种洗涤剂形成赤道胶束，其中酰基链围绕蛋白质的疏水带，确认现有的模型的洗涤剂溶剂化的膜蛋白。此外，出乎意料的是，PagP的细胞外和周质顶端表面与其他胶束中的洗涤剂的头基相互作用的时间分别为85%和60%，形成稳定数百纳秒的复合物。在某些情况下，一个PagP分子的顶面与另一个PagP分子周围的赤道胶束相互作用。在其他情况下，两个分子的PagP的顶端表面同时结合一个净洗涤剂胶束。在这些方式中，洗涤剂介导折叠PagP的非特异性聚集。这些模拟结果与动态光散射实验一致，其表明，在去污剂浓度>= 600 mM时，PagP诱导可能含有许多拷贝的PagP蛋白的大散射物质的形成。总之，这些模拟和实验结果指向一个潜在的通用机制的洗涤剂介导的蛋白质聚集。(C)2013爱思唯尔爱尔兰有限公司版权所有。
Because detergents are commonly used to solvate membrane proteins for structural evaluation, much attention has been devoted to assessing the conformational bias imparted by detergent micelles in comparison to the native environment of the lipid bilayer. Here, we conduct six 500-ns simulations of a system with >600,000 atoms to investigate the spontaneous self assembly of dodecylphosphocholine detergent around multiple molecules of the integral membrane protein PagP. This detergent formed equatorial micelles in which acyl chains surround the protein's hydrophobic belt, confirming existing models of the detergent solvation of membrane proteins. In addition, unexpectedly, the extracellular and periplasmic apical surfaces of PagP interacted with the headgroups of detergents in other micelles 85 and 60% of the time, respectively, forming complexes that were stable for hundreds of nanoseconds. In some cases, an apical surface of one molecule of PagP interacted with an equatorial micelle surrounding another molecule of PagP. In other cases, the apical surfaces of two molecules of PagP simultaneously bound a neat detergent micelle. In these ways, detergents mediated the non-specific aggregation of folded PagP. These simulation results are consistent with dynamic light scattering experiments, which show that, at detergent concentrations >= 600 mM, PagP induces the formation of large scattering species that are likely to contain many copies of the PagP protein. Together, these simulation and experimental results point to a potentially generic mechanism of detergent-mediated protein aggregation. (C) 2013 Elsevier Ireland Ltd. All rights reserved.